Pain

U of T, international researchers focus on 'surprisingly high' incidence of chronic pain in adolescents

Christopher.Sorensen — Tue, 07 Jan 2020 13:53:18 +0000

U of T, international researchers focus on 'surprisingly high' incidence of chronic pain in adolescents

Christopher.Sorensen Tue, 01/07/2020 - 08:53

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The five-year international research project, which looks to uncover a biological signature for chronic pain in adolescents, is the largest pediatric study of its kind (photo by Jesper Aggergaard via Unsplash)

Erin Vollick

Topic

Global Lens

Faculty of Dentistry

Global

Hospital for Sick Children

Lawrence S. Bloomberg Faculty of Nursing

Pain

Research & Innovation

An international research collaboration has been awarded a $9-million research grant from the U.S. National Institutes of Health to tackle the complex problem of chronic musculoskeletal pain in adolescents.

The five-year research project, involving two distinct phases and an international team of researchers from the ��߲ݴ�ý, the Hospital for Sick Children, Stanford University and Cincinnati Children’s Hospital, will work towards uncovering a biological signature for chronic pain, helping those for whom traditional therapies aren’t effective.

International in scope and global in its potential impact, the project represents an unprecedented opportunity to perform vital research on a largely unstudied population.

“This is the first pediatric study of this magnitude,” says project co-investigator Jennifer Stinson, professor in U of T’s Lawrence S. Bloomberg Faculty of Nursing and a nurse practitioner at the chronic pain clinic at the Hospital for Sick Children.

The study will shed light on a phenomenon not well understood. Up to five per cent of adolescents – that’s 3.5 million in the U.S. alone – suffer from chronic musculoskeletal pain. The pain can stem from anything from injuries to juvenile fibromyalgia and Ehlers-Danlos Syndrome, a condition affecting connective tissues in the body.

“Children’s chronic pain is really, really underappreciated in that the incidence of it is surprisingly high, but the awareness of it is surprisingly low,” says co-investigator Robert Coghill, director of the Center for Understanding Pediatric Pain and professor of pediatrics at Cincinnati Children’s Hospital Medical Center.

Not all pain is the same, though: A staggering 40 to 60 per cent of sufferers will be considered treatment-resistant. Those adolescents quickly grow into adults with chronic, untreatable pain. But by looking at chronic pain through an array of angles – brain imaging, quantitative sensory testing, immunology and psychology – the researchers hope to pinpoint which adolescents will or won’t respond to treatments, and what underlying factors may be at work in those outcomes.

The first phase of the project will gather these types of data from 250 adolescents aged 14 to 18 who suffer from chronic musculoskeletal pain.

“if we are able to capture enough measures across a whole slew of domains, we can then use unbiased machine learning and [big data] algorithms to predict whether patients will respond to treatment or not,” explains Massieh Moayedi, assistant professor at U of T’s Faculty of Dentistry, a co-investigator who brings expertise in pain and brain imaging to the project.

“A multimodal biomarker will allow us to classify those who are at high risk for pain persistence.”

If successful at pinpointing a chronic pain signature, a second phase of the study will commence in which data from a second cohort of 125 adolescent recruits will help validate the pain signature.

“This project is really unique,” says Stinson, who also leads the iOuch lab at Sick Kids. “If we can actually find this biological signature, we have a chance to do more precision medicine based on the phenotype of that child. We’ll be able to better tailor treatment.”

Laura Simons, a psychologist and associate professor at Stanford University with expertise in psychological factors influencing children’s pain, will lead the study.

“I’m very excited about the immune profiling,” says Simons, pointing to a burgeoning field of study that looks at the behaviour of immune cells after trauma or medical interventions such as surgery.

Equally, Simons is “curious to see whether some of our ‘pen and pencil measures’ [of psychology] will rise to the top, to see whether they are as informative as more invasive measures.”

While each of the teams will perform their series of tests on their adolescent recruits, Stanford University and the Stanford University Medical Centre will additionally collate data and perform data analysis on the results. The data will remain at Stanford, where the researchers will begin collating one of the world’s largest biobanks of multimodal paediatric pain data for future studies.

Patient recruitment for phase one of the study begins as early as this month.

The brain’s frontal lobe could be involved in chronic pain: U of T research

ullahnor — Thu, 24 May 2018 20:25:24 +0000

The brain’s frontal lobe could be involved in chronic pain: U of T research

ullahnor Thu, 05/24/2018 - 16:25

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Professor Min Zhuo has been studying invisible pain for the last two decades. He has discovered the brain's frontal lobe may be involved in chronic pain

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A ��߲ݴ�ý scientist has discovered the brain’s frontal lobe is involved in pain transmission to the spine. If his findings in animals bear out in people, the discovery could lead to a new class of non-addictive painkillers.

For 20 years, Min Zhuo, a professor of physiology in the Faculty of Medicine, has been intrigued by invisible pain, in particular chronic pain with no obvious cause. He has long suspected that the standard way of viewing spinal pain – it must come from injury or tissue inflammation – and the usual understanding of how to treat it – block it from entering the spinal cord – wasn’t telling the whole story.

Now, Zhuo has shown in mice and rats that some spinal pain actually begins in the brain’s frontal lobe, an area previously thought to be uninvolved. And he has shown how treating the pain in this area could be effective at preventing chronic pain. Zhuo published his results May 16 in the journal Nature Communication.

“When doctors can’t see anything wrong to cause chronic pain, often they think patients are making it up,” says Zhuo. “But pain that originates in the frontal lobe would be very different from pain that comes from a physical injury, like a herniated disc. There wouldn’t necessarily be any injury to see. That’s because our personality and emotions live in this region. If the frontal lobe can produce physical pain, that pain would be deeply tied to emotions like anxiety.”

Scientists already knew that the prefrontal cortex was in some way involved in pain because it would light up in scans of people in pain. But that activity was always thought to be symptom not cause, says Zhuo.

“When you have extreme anxiety, more neurotransmitters are released that end up causing pain in the spine,” he says. “Normal functions like walking shouldn’t be painful. But this flood of neurotransmitters sends the spine into hyper drive, and it starts treating ordinary sensations like pain. That could explain why anxiety can cause chest pain and make you think you’re having a heart attack. Or why some people experience pain when you touch them. I believe this helps to explain why emotional pain causes physical pain.”

The good news is that pain from the frontal lobe seems to be transmitted in a simple, direct way to the spine – making it relatively easy to shut down. Neurons in the frontal cortex send signals all the way down the spinal cord, says Zhuo, whereas pain signals from other areas of the brain are mediated by a complex network.

In animals, Zhuo found that pain was associated with increased neurotransmitters released from the frontal cortex. He was able to lessen pain by reducing the amount released. His next step is to test this process in people.

Those who suffer from anxiety along with neuropathic pain would likely benefit from a painkiller targeting the frontal lobe, says Zhuo.

The research was supported by the National Key Basic Science Research Project and the Natural Science Foundation of China.

Targeting chronic pain: U of T researcher identifies potential way to reduce pain

ullahnor — Tue, 08 Aug 2017 17:32:26 +0000

Targeting chronic pain: U of T researcher identifies potential way to reduce pain

ullahnor Tue, 08/08/2017 - 13:32

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One in five Canadians suffer from chronic pain. Loren Martin, a U of T Mississauga behavioural neuroscientist, has helped identify a molecule that researchers say could be responsible for chronic pain (photo by threephin via Flickr)

Nicolle Wahl

Author legacy

Nicolle Wahl

Topic

A molecule responsible for activating the body’s pain receptors has been identified by a U of T neuroscientist and an international team of researchers, offering hope to people suffering from chronic pain worldwide.

Despite the prevalence of chronic pain, the current options for pain relief are limited to opioids, which carry the possibility of addiction, overdoses and unpleasant side effects.

Loren Martin, an assistant professor of psychology at the ��߲ݴ�ý Mississauga, collaborated with colleagues from McGill University and the University of North Carolina and found that inhibiting one of the body’s proteins, known as epidermal growth factor receptor (EGFR), lessens the pain associated with nerve injury and inflammation in mice. Genetic mutations of EGFR were also linked to the development of head and jaw pain in people.

The researchers also found that one particular molecule, epiregulin, is implicated in EGFR-related chronic pain – those who had chronic pain had higher than normal levels of epiregulin.

They plan to explore the therapeutic potential of controlling epiregulin, since simply inhibiting the EGFR receptor has side effects of its own that may cause reluctance to use drugs that rely on this approach.

“By normalizing the body’s levels of epiregulin, we may be able to reduce sensitivity to pain and improve the quality of life for chronic pain sufferers,” said Martin, the study's lead author.

Their study appears in the Journal of Clinical Investigation this month.

Martin first became interested in pursuing this line of inquiry when he noted that cancer patients who were prescribed EGFR-inhibiting drugs reported a lessening of pain after taking the medication.

“The association of this receptor with small-cell lung cancer is well known, but we demonstrate that inhibition of this receptor is not unique to those suffering from cancer,” Martin said. “Instead, this receptor appears to be associated with general pain processing.”

A study done by his collaborators analyzed about 3,000 people and discovered that those who developed a particular type of chronic facial pain had a mutation in the EGFR receptor and in the gene coding for epiregulin. In the current study, an analysis of three human pain cohorts linked the epiregulin/EGFR pathway to chronic pain.

Martin then replicated those results in mice by inducing conditions that are accompanied by chronic pain and measuring the epiregulin levels in their blood.

“When we blocked the EGFR receptor with the inhibitors currently available, it reversed chronic pain in mice,” he said.

The research was supported by the Canadian Institutes for Health Research, the National Institutes of Health, the Australian National Health and Medical Research Council, the Louise and Alan Edwards Foundation and the Canadian Pain Society.

Torn ligaments, broken bones, muscle strains: U of T research finds athletes gain from pain

ullahnor — Wed, 25 Jan 2017 17:12:27 +0000

Torn ligaments, broken bones, muscle strains: U of T research finds athletes gain from pain

ullahnor Wed, 01/25/2017 - 12:12

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The findings could help coaches work with athletes to help them develop self-awareness, foster good training partnerships and psychologically prepare them for competition (photo by Martin Bazyl)

Katie Babcock

Author legacy

Katie Babcock

Topic

Breaking Research

Athletes

Pain

Faculty of Kinesiology and Physical Education

Sports

Pain not only helps athletes build self-awareness and improve their skills, but dealing with injuries also helps athletes create bonds with training partners and find a strong support system.

Kristina Smith, a graduate student in the Faculty of Kinesiology and Physical Education, researched the role of pain in sports by studying mixed martial arts (MMA), a hyper-explosive combat sport that involves striking and grappling.

Her findings could help athletes and coaches in all sports – from hockey to marathons.

“Pain is more than a physiological experience – it’s also a social and cultural phenomenon,” says Smith, who recently completed her master’s degree at the Faculty of Kinesiology and Physical Education.

“In everyday life we usually try to avoid or manage pain. But most athletes enter into a relationship with it to understand themselves and advance their skills.”

Mixed martial arts provided a unique context for studying pain – competitors inflict as much damage as possible using Muay Thai, sambo, boxing, kick boxing and jiu jitsu.

Smith studied seven athletes over four months through interviews, observation, video diaries and recordings of training sessions and fights.

She also trained with the fighters to experience pain first-hand.

“At first I was really intimidated, but I got the hang of it and became confident in my training. I went through my own injuries, and it really helped me to understand what the fighters were going through.”

So, how can coaches and athletes put these findings into practice?

Smith advises taking a broader look at reactions to pain and recommends using open communication to develop athletes’ self-awareness, help them foster trusting training partnerships and psychologically prepare them for competition.

“The coach at my gym would constantly talk about pain. He would model this behavior and make it okay for athletes to talk about it too. He turned it into a learning experience and this helped the athletes to grow personally and as a group,” she says.

Assistant Professor Katherine Tamminen, whose research focuses on sport psychology, supervised Smith’s research. Professor Michael Atkinson is Smith’s current PhD supervisor.

“Pain is very relational, and when one individual experiences it, it is also felt among teammates and spectators,” Atkinson says. “When others see athletes experience pain, they can relate to it at a deep level, and it can teach them how to manage it themselves.”

In the future, Smith plans to study pain in palliative care settings.

“We’re really just learning about people’s responses to, and uses of pain, as well as how pain is culturally constructed. People encounter pain in a full spectrum of ways. I hope to use my previous and future research to reveal more about the complex nature of pain.”

Training is key to ending opioid epidemic, says U of T expert

lavende4 — Tue, 18 Oct 2016 14:09:17 +0000

Training is key to ending opioid epidemic, says U of T expert

lavende4 Tue, 10/18/2016 - 10:09

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(Photo by John Moore/Getty Images)

Liam Mitchell

Author legacy

Liam Mitchell

Topic

In 2014, more than 700 people died in Ontario from opioid-related causes, making it the third-leading cause of accidental death in the province.

In response, the Ontario government has just announced a new comprehensive opioid strategy to develop new, evidence-based training modules and academic programs in conjunction with educational institutions, which will provide modernized training to all health-care providers who prescribe or dispense opioids.

The ��߲ݴ�ý has been at the forefront of the battle against opioid abuse. For the past four years, U of T's Faculty of Medicine has offered an innovative and award-winning course for physicians and other health-care providers on the safe prescribing of opioids. By the end of 2016, 480 participants will have completed the program offered through the continuing professional development office in the Faculty of Medicine.

Dr. Abhimanyu Sud, the course’s director and a lecturer in the department of family and community medicine, says the focus needs to be on delivering effective education.

“There is a huge demand from physicians for better education on prescribing opioids. You can see genuine worry about how to deal with this issue. But we should use the best educational methods available to deliver that information.”

The U of T course is delivered through a hybrid of online learning and in-person training. It begins with three live webinars that allow learners to respond in real time to questions posed by course instructors. Participants build their base level of knowledge on topics like the assessment of chronic pain and details about opioids themselves and then review complex case studies. Finally, they participate in a one-day workshop where they role-play scenarios they might confront in their practice, such as assessing for addiction.

Sud, who is a family physician with a specialized practice in chronic pain, initially came upon the field by surprise.

“I found that when I came out of medical school, I really hadn’t received a lot of training in prescribing opioids. And it was at a time when there was a shift from broadly prescribing opioids for treating chronic pain, because we thought they were harmless, to starting to see the negative consequences. We were all looking for clearer information and more guidance,” he says.

A large part of that guidance came in 2010 when the Canadian Guideline for Safe and Effective Use of Opioids for Chronic Non-Cancer Pain was first released. A new set of guidelines is expected to be released in 2017.

“Our participants get a thorough understanding of the guidelines, which forms the basis of our course. It’s a complex document, so we walk them through it to ensure they have the confidence of what it says and how best to use it,” says Sud.

The course is offered three times per year with the next session beginning in January 2017.

While most participants are family doctors, the course has drawn other medical specialists as well as nurse practitioners and addiction workers from across Canada. Five faculty members are helping to lead the course and plans are underway to offer the in-person workshops outside of Toronto.

“Our aim isn’t just to impart knowledge, but we really want to change how people conduct their practice. When we see practices change, that’s when we know we’re having an impact,” says Sud.

Anxiety and pain: two sides of the same synapse?

sgupta — Fri, 16 Jan 2015 11:12:49 +0000

Anxiety and pain: two sides of the same synapse? sgupta Fri, 01/16/2015 - 06:12

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"Patients with chronic pain are often anxious, and that if this pain lasts a long time many will suffer depression and lose hope," Zhuo says (photo by Sarah Joy via Flickr)

Jim Oldfield

Author legacy

Jim Oldfield

Topic

Subheadline

"When you have chronic pain, you develop anxiety. Because you have anxiety, you suffer more chronic pain," says Professor Min Zhuo

Researchers have known for a decade what patients have suspected much longer: chronic pain produces anxiety, and anxiety makes the pain worse. But why? Scientists have found tantalizing clues, including intense activity in the same part of the brain during both sensations. But an answer has been elusive.

Now, neuroscientists at the ��߲ݴ�ý have mapped a mechanism in the brain’s anterior cingulate cortex, or ACC, that could explain the link between anxiety and chronic pain.

Min Zhuo is a professor in the department of physiology at U of T and the Canada Research Chair in Pain and Cognition. Zhuo and his lab recently published a paper in the journal Neuron that showed how neuroplasticity – the brain’s ability to physically re-organize itself in response to experience – can spur the interplay between chronic pain and anxiety. They also showed that a drug they developed for chronic pain can limit anxiety.

Zhuo spoke with Faculty of Medicine writer Jim Oldfield about his findings and what they could mean for patients.

What’s the link between pain and cognition in your work?
Most chronic pain researchers study pain as a sensory experience. They think that if we reduce the physical pain, the patient will be better. But I think we need to look at both the mental and physical in the study of pain. Recently we’ve seen more acknowledgment that patients with chronic pain are often anxious, and that if this pain lasts a long time many will suffer depression and lose hope. As well, more researchers are moving away from the idea that mental disorders are just genetic – i.e., you have a bad gene and that’s why you have disease. In my view, if chronic pain causes enough physical change in the brain, anyone can behave like a mentally ill patient. So to better understand and treat pain we need to look at its physical cause but also cognition and mental health, or emotional well-being.

What findings does the Neuron paper describe?
We found a possible explanation for why chronic anxiety and pain make each other worse. Neurons communicate through synapses, which are structures that convey nerve impulses from one neuron to another. These synapses are plastic, meaning they change physically in response to stimuli. Repeated experiences can reinforce these changes and over time the physical changes can become permanent. It’s like a learned memory. And when that happens, you can experience a sensation without an underlying cause. You’ve probably heard of amputees who have pain in a limb that doesn’t exist. Well, we found a similar “learned memory” process for anxiety, in a different part of the same synapse where we see activity linked to chronic pain.

So when these two functions become partners, they make each other worse. When you have chronic pain, you develop anxiety. Because you have anxiety, you suffer more chronic pain. This is the first evidence that anxiety is linked to long-lasting changes at synapses.

Is there a way to short-circuit this process?

We identified a channel or genetic process called HCN that maintains this anxious learning. So theoretically, if we find an inhibitor to erase the long-term potentiation for anxiety – the learned memory – we should be able to reduce anxiety through this channel. But a big challenge is that drugs in the central nervous system often produce side effects. The HCN channel is also expressed in heart and other types of cells, so any drug targeting this channel would have to be selective for neurons.

Fortunately, a drug we’ve been developing for pain called NB001 inhibits a protein called AC1 that is upstream from HCN, and it does so in a way that is selective for neural cells. It’s a very promising therapy for chronic pain and anxiety.

What are the challenges in bringing this drug to market?
Our research is still at the pre-clinical stage. But it’s very difficult to move drug discovery forward, in part due to the world economic situation. There are few angel funders because of the recession. Big Pharma is risk-averse. NGOs support experimental research, but their funds are very tight. On the bright side, we have teamed with investors and researchers internationally on clinical tests in cancer patients. Many cancer patients have pain that is badly managed; in the late stages they’re almost asleep with high-dose opiates. Others don’t get enough medicine and live with terrible pain and anxiety. My hope is that one day we can treat these patients with a drug that works.

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